Anxiolytic Substances Research Articles

Overload and spirituality of the informal caregiver: a narrative review

Not infrequently, the caregivers involved prioritize the dependent person and forget their own care because of the complexity of daily tasks, as well as leaving aside their needs and activities that provide satisfaction in living. Over time, this can cause overload to the caregiver. Spirituality provides subjective elaboration of relevance to existence, which increases the motivation for facing and overcoming adversities. This research aims to conduct a narrative review of studies on the topics of overload, care and spirituality of the informal caregiver. To do so, the topics of overload, spirituality and the confrontation by informal caregivers were addressed according to the previous themes. The literature points out that caring for an elderly person can bring physical and emotional overload, and the caregiver is more likely to develop depressive symptoms, anxiety, smoking, worse health, and to consume hypnotic and anxiolytic substances. Thus, spirituality is important not only for the help of facing diseases, but for the coping with adversities that appear in the life of the informal caregiver. There is a need for more studies and public policies on this theme, since there is a large gap in literature today.

Association between Anxiety Status and Hydration Status in Spanish University Students.

Anxiety disorders are a very common psychiatric pathology among young university students, and the strategies for its mitigation are limited to the consumption of anxiolytic substances. Adequate hydration is essential for staying healthy, as water is the main component of the human body and of several physiological processes. A state of dehydration, in addition to a negative water balance, has serious consequences on health status. We aimed to determine the association between the degree of anxiety and the level of hydration in Spanish university students. A cross-sectional, observational research study with a sample of 65 female university students was conducted. Over 90% of the study population shows anxiety levels above the 95th percentile. The individuals with anxiety above the 95th percentile showed a negative water balance. The consumption of coffee and herbal teas shows correlations with state anxiety and trait anxiety.

Discriminative stimulus and reinforcing effects of diclazepam in rodents

Diclazepam, a designer benzodiazepine, is a lesser-known novel anxiolytic substance and a structural analog of diazepam. Although several case studies have reported the adverse effects of diclazepam, their potential impacts remain unknown. Therefore, this study aimed to determine the effects of diclazepam in rodents using drug discrimination, locomotor activity, self-administration (SA), and conditioned place preference (CPP) tests. Sprague-Dawley rats (male, 8 weeks old, weighing 220–450 g, n = 12 per group) and C57BL/6 mice (male, 7 weeks old, weighing 20–25 g, n = 7–8 per group) were administered alprazolam, morphine, and diclazepam. Diclazepam fully elicited alprazolam-appropriate dose-dependent lever responses (>80 %) similar to those of alprazolam. In rats administered 0.5 mg/kg of morphine, a partial substitution (80 %–20 %) was observed. Mice receiving intraperitoneal injections of diclazepam (0.05, 0.2, and 2 mg/kg) showed decreased locomotor activity. In the SA experiment, mice that self-administered intravenous diclazepam (2 μg/kg/infusion) showed significantly higher infusion and active lever responses compared to the vehicle group. No statistically significant rewarding effects of diclazepam at the doses of 0.2 and 2 mg/kg evaluated using the CPP paradigm were found. In conclusion, diclazepam has reinforcing effects and shares the interoceptive effects of alprazolam. Therefore, legal restrictions on the use of diclazepam should be carefully considered.

Differential effects of the translocator protein 18 kDa (TSPO) ligand etifoxine and the benzodiazepine alprazolam on startle response to predictable threat in a NPU-threat task after acute and short-term treatment

RationaleBenzodiazepines have been extensively investigated in experimental settings especially after single administration, which mostly revealed effects on unpredictable threat (U-threat) rather than predictable threat (P-threat). Given the need for pharmacological alternatives with a preferable side-effect profile and to better represent clinical conditions, research should cover also other anxiolytics and longer application times.ObjectivesThe present study compared the acute and short-term effects of the translocator protein 18 kDa (TSPO) ligand etifoxine and the benzodiazepine alprazolam on P-threat and U-threat while controlling for sedation.MethodsSixty healthy male volunteers, aged between 18 and 55 years, were randomly assigned to receive a daily dose of either 150 mg etifoxine, 1.5 mg alprazolam, or placebo for 5 days. On days 1 and 5 of intake, they performed a NPU-threat task including neutral (N), predictable (P), and unpredictable (U) conditions, while startle responsivity and self-reports were studied. Sedative effects were assessed using a continuous performance test.ResultsNeither alprazolam nor etifoxine affected startle responsivity to U-threat on any of the testing days. While etifoxine reduced the startle response to P-threat on day 1 of treatment for transformed data, a contrary effect of alprazolam was found for raw values. No effects on self-reports and no evidence of sedation could be observed for either drug.ConclusionsNone of the anxiolytic substances had an impact on startle potentiation to U-threat even after several days of intake. The effects of the anxiolytics on startle responsivity to P-threat as well as implications for future studies are discussed.

Neurochemical and Behavioral Consequences of Ethanol and/or Caffeine Exposure: Effects in Zebrafish and Rodents.

Zebrafish are increasingly being utilized to model the behavioral and neurochemical effects of pharmaceuticals and, more recently, pharmaceutical interactions. Zebrafish models of stress establish that both caffeine and ethanol influence anxiety, though few studies have implemented coadministration to assess the interaction of anxiety and reward-seeking. Caffeine exposure in zebrafish is teratogenic, causing developmental abnormalities in the cardiovascular, neuromuscular, and nervous systems of embryos and larvae. Ethanol is also a teratogen and, as an anxiolytic substance, may be able to offset the anxiogenic effects of caffeine. Co-exposure to caffeine and alcohol impacts neuroanatomy and behavior in adolescent animal models, suggesting stimulant substances may moderate the impact of alcohol on neural circuit development. Here, we review the literature describing neuropharmacological and behavioral consequences of caffeine and/or alcohol exposure in the zebrafish model, focusing on neurochemistry, locomotor effects, and behavioral assessments of stress/anxiety as reported in adolescent/juvenile and adult animals. The purpose of this review is twofold: (1) describe the work in zebrafish documenting the effects of ethanol and/or caffeine exposure and (2) compare these zebrafish studies with comparable experiments in rodents. We focus on specific neurochemical pathways (dopamine, serotonin, adenosine, GABA), anxiety-type behaviors (assessed with a novel tank, thigmotaxis, shoaling), and locomotor changes resulting from both individual and co-exposure. We compare findings in zebrafish with those in rodent models, revealing similarities across species and identifying conservation of mechanisms that potentially reinforce coaddiction.

Caffeine-induced bradycardia, death, and anxiety-like behavior in zebrafish larvae

Caffeine, a major ingredient of coffee and other drinks, causes minimal health problems. However, excessive caffeine intake may induce emotional and cardiac events. Studies on zebrafish larvae are considered useful for understanding drug poisoning because they can be used for multiple simulations. The locomotion (swim distance) of zebrafish larvae exposed to varying concentrations of caffeine was measured using a light–dark test and an automatic video-tracking system. Mortality and heart rates were assessed 4 and 24 h after caffeine exposure and 24 h after caffeine removal. The heart and survival rates were reduced by exposure to caffeine of > 300 mg/L after 24 h in a dose-dependent manner; this was attenuated by caffeine removal at 4 h. Caffeine reduced the heart rate and survival considerably at 1000 mg/L, supporting the notion of caffeine-induced cardiac arrest resulting from bradycardia. The locomotion of zebrafish larvae during six alternating cycles of light–dark exposure was slower during light periods and faster during dark periods; 100–300 mg/L caffeine increased and decreased locomotion during light and dark cycles, respectively, with high inter-cycle reproducibility. Given the anxiogenic effect of caffeine and light preference of zebrafish larvae, caffeine-induced changes in light–dark cycles could provide a new reliable marker for anxiety. Therefore, the “light–dark locomotion test” employed in this study is valuable for research on anxiogenic or anxiolytic substances. The test may allow simultaneous and automatic analysis of the locomotion of many fish under multiple conditions, thereby enabling evaluation of dose–response effects of caffeine.

Alprazolam addiction: The case study

IntroductionAlprazolam is an anxiolytic, a benzodiazepine derivative of the middle duration of action. It is one of the most frequently prescribed medication for the treatment of anxiety and panic disorder. Under the action of a drug, a person feels incredible ease, a sense of euphoria, absence of problems, a sense of safety.ObjectivesA 55-year woman was admitted to psychiatric clinic in Ivano - Frankivsk.MethodsShe was assesed by the clinicopsychopatological method (clinical interview) and additional methods (MRI, EEG, pathopsycological assessment).ResultsThe main findings were: atactic procession, tremor of the limbs and the whole body, poor attention, speech impairment, retarded thinking, fixation and reproductive amnesia with the components of progressive amnesia, change handwriting. The mood is lowered with unstable affect, lack of insight. She reported burning and tingling of the head as a main problem. She developed amotivation, bad activity and drowsiness, bradycardia, decreased blood pressure. She took Alprazolam during a period of 1,5 year in gradually increasing doses. The last dose was 12 tablets of Alprazolam per day. The patient was consulted again in a year. She does not take Alprazolam. She takes valproate and escitalopram. She did not demonstrate severe neurological symptoms which were seen a year ago.ConclusionsThus, though alprazolam is one of the best anxiolytic substance it should be prescribed only by the doctor for a short course (no more than 4-5 weeks). The treatment must include psychoeducation in order to make patients be aware about possible addiction and unsafety of prolonged and uncontrolled usage of alprazolam.DisclosureNo significant relationships.

Development of a Method for Determination of Related Impurities in GML-3 Drug Substance: A New Compound with Anxiolytic Properties

A method for determination of related impurities in the new anxiolytic drug substance GML-3 was developed. HPLC and TLC techniques that could identify starting materials and synthetic intermediates and quantify them and unidentified impurities with contents of 0.05% and less in the drug substance were developed. The proposed techniques could be used further for quality control of GML-3 drug substance.

Availability of Internationally Controlled Essential Medicines in the COVID-19 Pandemic

Section 2 of the 2019 World Health Organization Model List of Essential Medicines includes opioid analgesics formulations commonly used for the control of pain and respiratory distress, as well as sedative and anxiolytic substances such as midazolam and diazepam. These medicines, essential to palliative care, are regulated under the international drug control conventions overseen by United Nations specialized agencies and treaty bodies and under national drug control laws. Those national laws and regulations directly affect bedside availability of Internationally Controlled Essential Medicines (ICEMs). The complex interaction between national regulatory systems and global supply chains (now impacted by COVID-19 pandemic) directly affects bedside availability of ICEMs and patient care. Despite decades of global civil society advocacy in the United Nations system, ICEMs have remained chronically unavailable, inaccessible, and unaffordable in low- and-middle-income countries, and there are recent reports of shortages in high-income countries as well. The most prevalent symptoms in COVID-19 are breathlessness, cough, drowsiness, anxiety, agitation, and delirium. Frequently used medicines include opioids such as morphine or fentanyl and midazolam, all of them listed as ICEMs. This paper describes the issues related to the lack of availability and limited access to ICEMs during the COVID-19 pandemic in both intensive and palliative care patients in countries of all income levels and makes recommendations for improving access.

Three- and bi-dimensional analyses of the shoaling behavior in zebrafish: Influence of modulators of anxiety-like responses

Social behaviors are key components that play adaptive roles in various species, including humans. The zebrafish (Danio rerio) is a social species and the shoaling behavior can be pharmacologically manipulated either by anxiogenic or anxiolytic substances, providing translatable data in neuropsychiatric research. Here, we aimed to characterize the shoaling behavior in zebrafish under different pharmacological manipulations in a three-dimensional (3D) perspective using the spatial coordinates of the fish positions. Temporal and spatial reconstructions of shoal occupancy were performed after exposure to conspecific alarm substance (CAS) and caffeine (CAF) (anxiogenic substances) or diazepam (DZP) (a classical anxiolytic drug). Behavioral 3D analyses and spatiotemporal reconstructions of the shoaling behavior revealed that both CAS and CAF decreased the shoal volume, the average fish distance to the centoid point, and increased shoal geotaxis, but only CAS reduced the inter-fish distance when compared to control (CTRL). Conversely, DZP group showed increased shoal volume and inter-fish distance. Because substantial differences were verified when the shoaling response was analyzed in 3D and 2D perspectives, we reinforce the use of 3D reconstructions of fish positions to assess how different manipulations affect the social behavior of zebrafish. The novel procedure described here represents an easy-to-use, inexpensive, and alternative tool to perform a spatiotemporal reconstruction of the shoal occupancy under different pharmacological manipulations, complementing the existing quantification of locomotion activity of multiple fish.

Neuropeptide S Induces Acute Anxiolysis by Phospholipase C-Dependent Signaling within the Medial Amygdala.

Neuropeptide S (NPS) is an important anxiolytic substance of the brain. However, the signaling pathways downstream of NPS receptor (NPSR) activation, underlying the behavioral effect of NPS, remain largely unknown. Here, we show that bilateral microinfusion of NPS (0.2 nmol/0.5 μl) into the medial amygdala (MeA) of male adult Wistar rats reduced anxiety-related behavior on both the elevated plus-maze and the open field. Moreover, as shown in amygdala tissue micropunches intracerebroventricular infusion of NPS (1 nmol/5 μl) (1) evoked phosphorylation and synthesis of CaMKIIα in relation to reference protein β-tubulin representing Ca2+ influx, and (2) induced phosphorylation of mitogen-activated protein kinase ERK1/2. The NPS-induced anxiolysis was prevented by local inhibition of phospholipase C signaling using U73122 (0.5 nmol/0.5 μl) in the MeA, indicating the behavioral relevance of this pathway. Conversely, local pharmacological blockade of adenylyl cyclase signaling using 2',5'-dideoxyadenosine (12.5 nmol/0.5 μl) failed to inhibit the anxiolytic effect of NPS infused into the MeA. Hence, NPS promotes acute anxiolysis within the MeA dependent on NPSR-mediated phospholipase C signaling. Taken together, our study extends the knowledge about the intracellular signaling mechanisms underlying the potent anxiolytic profile of NPS.

EVALUATION OF ANXIOLYTIC EFFECT OF MELILOTUS OFFICINALIS EXTRACTS IN MICE

Objective: Anxiety is one of the most common and serious mental illness affecting humankind and its extensiveness is on the rise at an alarming rate. Anxiolytic substances are highly acclaimed in the ranking of the most utilized drugs by human. The clinical applications of most widely used anxiolytic agents, that is, benzodiazepines are restricted by their undesirable side effects. Therefore, the development of new pharmacological agents for the treatment of this problem is well justified. Among medicinal plants, Melilotus officinalis (yellow sweet clover) has been recommended for relief of insomnia, convulsions, and as nervine tonic in traditional system of medicine. Nevertheless, no pharmacological studies have thus far evaluated its anxiolytic effect. Therefore, the aim of this study was to evaluate antianxiety effect of different extracts of M. officinalis in mice.Methods: The extracts of roots and aerial parts of the plant were prepared according to the polarity, that is, petroleum ether, chloroform, ethanol, and water. The anxiolytic effects of petroleum ether, chloroform, ethanol, and aqueous extract of aerial parts and roots of the plant (50, 100, and 200 mg/kg, p.o) were examined in albino mice using elevated plus maze (EPM) and mirror-chamber models of anxiety. High-performance thin layer chromatography (HPTLC) studies were carried out using toluene: Acetone: Formic acid as mobile phase.Results: Various extracts prepared from roots did not produce significant effect in both the models, whereas the ethanol extract prepared from aerial parts at 100 and 200 mg/kg showed a significant anxiolytic effect as compared to control and standard group. The petroleum ether, chloroform, and water extracts (50, 100, and 200 mg/kg) of the aerial parts of the plant did not produce meaningful effects in this study. HPTLC analysis of the ethanol extract revealed the presence of nine components.Conclusion: These results suggest that the ethanol extract of aerial parts of M. officinalis plant has statistically significant dose-dependent antianxiety activity which can be attributed to the presence of coumarin, and flavonoid compounds in it.

Sedative effects of intranasal oxytocin in rabbits and rhesus monkeys.

Oxytocin is a hormone therapeutically used mainly for its peripheral effects during pregnancy in the uterus and breasts. However, additional central effects, i.e. anxiolytic effect, decreased level of social stress and increased empathy have been also observed. Hence, the aim of our study was to evaluate if nasal oxytocin can be used as anxiolytic substance in rhesus monkeys (n=20) and rabbits (n=20). Simultaneously, mean arterial blood pressure, arterial oxygen saturation of hemoglobin and pulse rate were monitored in all the evaluated animals. While rabbits lost righting reflex, monkeys developed a dose-dependent loss of aggressiveness and/or anxiety as evaluated by behavioral methods (aggressive behavior was classified as non-sedated - sedated - strongly sedated).

Profiles of Youths With PTSD and Addiction

ABSTRACTObjective: Understanding the relationship between PTSD and addiction in adolescents may dramatically improve evidence-based practice in child psychiatry. We hypothesized that in a sample of substance addicted youth, PTSD would correlate with (1) female gender and racial minority status, (2) preference for anxiolytic substances, (3) higher burden of self injury and suicide attempts, and (4) earlier age of first use. Methods: One-hundred and ninety-five adolescents (52% female, ages 14–18) were court-referred to residential treatment and assessed at intake. Multi-informant data regarding Axis I diagnostic status and other clinical variables were collected via rater-administered, semi-structured interviews; medical chart review; and youth, parent, and clinician reports. Differences between subjects were evaluated using Fisher's exact test for binary variables or Kruskal-Wallis Chi-Square Test. Results: Substance dependent youth with comorbid PTSD were significantly more likely to be female and Latino. PTSD was correlated with preference for alcohol, narcotics, tranquilizers and inhalants. In addition, PTSD was correlated with higher burden of self-injury and suicidal behavior. Youth with PTSD were also more likely to have begun using before age 13 and reported that PTSD symptoms preceded first use. Conclusions: Girls and Latinos may be particularly vulnerable in developing comorbid substance dependence and PTSD. Drug preferences among youth with PTSD may reflect tendencies to target symptoms such as hypervigilance and anxiety. The recognition and early intervention among youth with trauma could prevent early first use and eventual substance dependency.

Naturally occurring anxiolytic substances from aromatic plants of genus citrus

Currently, anxiety is one of the most common mental disorders affecting humanity and its prevalence is increasing. Anxiolytic substances occupy a prominent post in the ranking of the most utilized drugs by man. However, the anxiolytic drugs have an unfavorable risk/benefit ratio, especially benzodiazepines. Several medicinal plants have been used in traditional folk medicine for their anxiolytic or sedative properties. It is well reported in the literature that aromatic substances have the power to influence emotional states in humans. Several plants rich in essential oil have been used in the treatment of anxiety. In addition, a great number of essential oils are currently in use as aromatherapy agents to relieve stress and depression. These oils are considered a holistic complementary therapy utilized for increased comfort and reduce stress. For this reason, we performed a literature review used papers indexed in Elsevier Science Direct and PubMed a source of research. The dates were collected of reviewed studies from 2000 to 2011 using essential oils of genus citrus with anxiolytic effects in preclinical models and clinical studies. Ethnopharmacological data has confirmed the popular use of plant species of the genus Citrus with sedatives, hypnotics, tranquilizers and anti-epileptics activities to treat disorders of the central nervous system. Given these assumptions, this paper aims to describe the principal evidence in the literature about the use of essential oils of genus citrus with anxiolytic effects in preclinical models and clinical studies. Key words: Genus citrus, anxiolytic effects, preclinical models, clinical studies of anxiety.

Physicochemical properties of and analytical method for the original anxiolytic substance GB-115

GB-115 is an original peptide anxiolytic with the structure N-(6-phenylhexanoyl)glycyl-L-tryptophan amide that has been developed at Zakusov State Institute of Pharmacology (Moscow). The physicochemical properties of GB-115 parent substance were studied. Analytical procedures for it were elaborated. General pharmacopoeial quality characteristics have been determined. UV, IR, and NMR spectra have been measured. A method for determining foreign impurities in GB-115 parent substance that is based on HPLC was developed.

Anxiolytic-like effects of human amniotic fluid and its fatty acids in wistar rats

Odors from amniotic fluid produce signs of calmness in mammals suggesting some anxiolytic-like properties. Experimental models, such as the defensive burying, elevated plus maze, and open field tests offer well-controlled approaches to the study of putative anxiolytic substances using rats. Using gas chromatography-mass spectrometry, we first identified eight fatty acids (lauric, myristic, palmitic, palmitoleic, stearic, oleic, elaidic, and linoleic acids) as consistently present in human amniotic fluid. We then used the defensive burying and elevated plus maze tests to compare the action of diazepam (2 mg/kg), fresh amniotic fluid, and a mixture of its fatty acids with two vehicles (i.e. propylene glycol and centrifuged amniotic fluid with a low fatty acid content). No significant differences in estradiol or progesterone content were found between fresh amniotic fluid and centrifuged amniotic fluid using the microparticle enzyme immunoassay. Compared with the vehicle, diazepam, fresh amniotic fluid, and the fatty acid mixture increased burying latency, reduced cumulative burying, and increased the time spent in the open arms of the elevated plus maze in both sexes without altering general locomotor activity. We conclude that the fatty acids contained in human amniotic fluid exert anxiolytic-like effects, with minimal or no participation of female gonadal steroids.

ChemInform Abstract: A New and Efficient Synthetic Route for the Anxiolytic Agent CL285032.

AbstractAn efficient alternative access to title compound (VI), an anxiolytic substance currently under investigation as a possible treatment for canine noise phobia associated anxiety, is presented.

Smoking, arousal, and affect: The role of anxiety sensitivity

Purpose Despite evidence that smoking elevates peripheral autonomic nervous system activity, cigarette smokers commonly report smoking to reduce negative affect, or “calm down.” Studies suggest that anxiety sensitivity is positively associated with the use of anxiolytic substances, but anxiety sensitivity is also characterized by aversive responding to elevations in physiological arousal. As such, anxiety sensitivity may be an important factor in the study of smoking, affect, and arousal. Method Smokers smoked cigarettes in two experimental sessions: a Stressful Speech Condition and a No Stress Condition. Psychophysiological and self-report served as within-subjects, repeated measures. Results Findings revealed that smoking reduced anxiety in high anxiety sensitive smokers who smoked during a stressful situation, but not a no stress situation. Low anxiety sensitive smokers endorsed anxiolysis in both conditions. Conclusions Results suggest that high anxiety sensitive smokers may be sensitive to the physiologically arousing effects of smoking in low stress, low arousal, situations.

Oxytocin reduces anxiety via ERK1/2 activation: local effect within the rat hypothalamic paraventricular nucleus

The neuropeptide oxytocin (OT) modulates social behaviours and is an important anxiolytic substance of the brain. However, sites of action and the intracellular signalling pathways downstream of OT receptors (OTR) within the brain remain largely unknown. In the present studies, we localized the anxiolytic effect of OT by bilateral microinfusion of OT (0.01 nmol/0.5 microL) into the hypothalamic paraventricular nucleus (PVN) in male rats using both the elevated plus-maze and the light-dark box. Moreover, intracerebroventricular administration of OT, but not of the related neuropeptide vasopressin (VP), dose-dependently activated the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade. Specifically, OT induced the phosphorylation of Raf-1, MEK1/2 and ERK1/2 in the hypothalamus in vivo and in hypothalamic H32 neurons via EGF receptors. OT-induced ERK1/2 phosphorylation was immunohistochemically localized within VP neurons of the PVN and the supraoptic nucleus. Importantly, the anxiolytic effect of OT within the PVN was prevented by local inhibition of the MAP kinase cascade with a MEK1/2 inhibitor (U0126, 0.5 nmol/0.5 microL) locally infused prior to OT, indicating the causal involvement of this intracellular signalling cascade in the behavioural effect of OT. OT effects within the hypothalamus may have far-reaching implications for the regulation of emotionality and social behaviours and, consequently, for the development of possible therapeutic strategies to treat affective disorders. Thus, OTR agonism or activation of the ERK1/2 cascade, specifically within the hypothalamus, may provide therapeutically relevant mechanisms.